Phase i clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma Journal Article
| Authors: | Konner, J.; Grisham, R. N.; Park, J.; O'Connor, O. A.; Cropp, G.; Johnson, R.; Hannah, A. L.; Hensley, M. L.; Sabbatini, P.; Mironov, S.; Danishefsky, S.; Hyman, D.; Spriggs, D. R.; Dupont, J.; Aghajanian, C. |
| Article Title: | Phase i clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma |
| Abstract: | Purpose To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients and Methods Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16.120 mg/m2). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m2. Results Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m2. PK data were linear from 16 to 100 mg/m2, with proportional increases in mean Cmax and AUCtot as a function of dose. Full PK analysis (mean±SD) at 100 mg/m2 revealed the following: half-life (t.)=9.1± 2.2 h; volume of distribution (Vz)=119±41 L/m2; clearance (CL)=9.3±3.2 L/h/m2. MTBF (n=9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m2. Tumor shrinkage (n=2, lymphoma), stable disease >3 months (n=5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n=1, colorectal cancer/CEA) were observed. Conclusion KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m2 weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862. © 2012 Springer Science+Business Media, LLC. |
| Keywords: | adult; aged; middle aged; neoplasms; leukocytes, mononuclear; lymphoma; microtubules; solid tumors; epothilones; epothilone d; tubulin modulators; epothilone; kos-862 |
| Journal Title: | Investigational New Drugs |
| Volume: | 30 |
| Issue: | 6 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2012-12-01 |
| Start Page: | 2294 |
| End Page: | 2302 |
| Language: | English |
| PUBMED: | 22072399 |
| PROVIDER: | scopus |
| DOI: | 10.1007/s10637-011-9765-7 |
| PMCID: | PMC4003559 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 May 2013" - "CODEN: INNDD" - ":doi 10.1007/s10637-011-9765-7" - ": Chemicals/CASEpothilones; Tubulin Modulators; desoxyepothilone B" - "Source: Scopus" |
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156Konner -
262Sabbatini -
37Mironov -
357Park -
170Grisham -
290Hensley -
354Hyman -
539Danishefsky -
609Aghajanian -
325Spriggs
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